title: Molecular basis for the regulation of hypoxia-inducible factor-1α levels by 2-deoxy-D-ribose.
abstract: The angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, inhibits the upregulation of hypoxia-inducible factor (HIF) 1α, BNIP3 and caspase-3 induced by hypoxia. In the present study, we investigated the molecular basis for the suppressive effect of 2-deoxy-D-ribose on the upregulation of HIF-1α. 2-Deoxy-D-ribose enhanced the interaction of HIF-1α and the von Hippel-Lindau (VHL) protein under hypoxic conditions. It did not affect the expression of HIF-1α, prolyl hydroxylase (PHD)1/2/3 and VHL mRNA under normoxic or hypoxic conditions, but enhanced the interaction of HIF-1α and PHD2 under hypoxic conditions. 2-Deoxy-D-ribose also increased the amount of hydroxy-HIF-1α in the presence of the proteasome inhibitor MG-132. The expression levels of TP are elevated in many types of malignant solid tumors and, thus, 2-deoxy-D-ribose generated by TP in these tumors may play an important role in tumor progression by preventing hypoxia-induced apoptosis.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-852, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tajitsu
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Minami
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Shinsato
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
mesh_terms: D015153:Blotting, Western; D003855:Deoxyribose / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D003855:Deoxyribose; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human